Isononyl alcohol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report equivalent or similar to OECD guideline (414): GLP.

Data source

Reference

Reference Type:

publication

Title:

Differential prenatal toxicity of one straight-chain and five branched-chain primary alcohols in rats

Author:

J. Hellwig and R. Jackh

Year:

1997

Bibliographic source:

Food and Chemical Toxicology. 35:489-500

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

only 10 animals used per group

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Isononyl alcohol

EC Number:

248-471-3

EC Name:

Isononyl alcohol

Cas Number:

27458-94-2

Molecular formula:

C9H20O

IUPAC Name:

3,5,5-trimethylhexan-1-ol

Details on test material:

- Name of test material (as cited in study report): isononanol type 1 and type 2
- Physical state: liquid

- 2 different isononanols were used, referred to as type 1 and type 2
Type 1 consisted of roughly equivalent amounts of 3,4-, 4,6-, 3,6-, 3,5-, 4,5- and 5,6-dimethylheptanol-1.
Type 2 consisted of 4,5-dimethylheptanol-1, 4-methyloctanol-1, 3-ethylheptanol-1, 6-methyloctanol-1, and 3-ethyl-4-methylhexanol-1.

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 68-85 days old
- Weight at study initiation: 214-233 g
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Chemicals were freshly prepared for gavage administration every day in aqueous emulsions under rapid stirring in double-distilled water containing approximately 0.005% Cremophor EL as an emulsifier

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/4
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnany

Duration of treatment / exposure:

From day 6 to day 15 post conception

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 158, 790, 1580
Basis:
analytical conc.
mg/kg/day isodecanol

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 144, 720, 1440
Basis:
analytical conc.
mg/kg/day isononanol type 1

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0, 130, 650, 1080
Basis:
analytical conc.
mg/kg/day isononanol type 2

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: study termination


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- weight of uterus before opening
- number of corpora lutea
- number of implantations
- live fetuses
- dead implantations
- early resorptions
- late resorptions
- dead fetuses

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: /half per litter
- Head examinations: Yes:

Statistics:

Dunnett’s test and Fisher’s exact test were used for evaluating data.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal effects generally included decreased body weight gain, apathy, nasal discharge, and signs of CNS depression.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Remarks:

isononanol type 1

Effect level:

720 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Remarks:

isononanol type 1

Effect level:

720 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

NOAEL

Remarks:

isononanol type 2

Effect level:

650 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

4

Dose descriptor:

NOAEL

Remarks:

isononanol type 2

Effect level:

650 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Embryotoxicty was not examined in this study.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In this study, isononanol type 1 (consisting of isomers with a moderate degree of branching (dimethyl heptanols) and approximately 16% isodecanol), isononanol type 2 (consisting of isomers with a low degree of branching (dimethyl heptanols and methyl octanols), were evaluated for their potential to induce developmental toxicity.  All chemicals were orally administered daily to pregnant dams during gestation day 6 through 15.

Isononanol type 1 (0, 144, 720, or 1440 mg/kg/day) at the highest dose was lethal for all 10 dams.  At 720 mg/kg bw/day effects on the dams consisted of unsteady gait, nasal discharge, initially reduced food consumption and effects on body weight parameter including retarded body weight gain during treatment.  No effects on the fetus were observed at this dose. 

Isononanol type 2 (0, 130, 650, 1080 mg/kg/day) was lethal for 3 dams at 1440 mg/kg bw/day.  Further marked effects consisted of impaired state of health including abdominal or lateral position, unsteady gait and apathy, reduced food consumption, effects on body weight parameters including body weight losses.  At 650 mg/kg bw/day, there were no statistically significant effects on the fetus.